title: Identification of 1-chloro-2-formyl indenes and tetralenes as novel antistaphylococcal agents exhibiting sortase A inhibition.
abstract: Tetralene and indene compounds have shown inhibitory activity against human pathogen, Mycobacterium tuberculosis. Their potential use as antistaphylococcal agent against drug-resistant Staphylococcus aureus has not been explored so far. We determined in vitro antistaphylococcal activity and mechanism of action of these compounds as sortase A inhibitors through in silico analysis followed by biological assays. Tetralene and indene series were tested against S. aureus strains MTCC96, MRSA, and VA30. Three compounds showed significant reduction in MIC in both wild-type and drug-resistant S. aureus strains. In silico absorption, distribution, metabolism, excretion, and toxicity analysis of identified leads and cytotoxicity testing with colorimetric method using Vero and WRL-68 cell lines showed no significant cytotoxic effects. Molecular docking of these molecules with sortase A (PDB: 2KID) showed H-bond interaction with functional site residue Arg197 of sortase A. Sortase A inhibition assay was developed by expressing SrtA∆N from S. aureus strain MTCC96. Tetralene and indene compounds were found to have sortase A inhibitory potential. S. aureus strain MTCC96 treated with these compounds showed surface-sorting inhibition of fibronectin-binding protein and reduction in adherence to host extracellular matrix protein, fibronectin. 1-Chloro, 2-formyl, 6-methoxy, 1-tetralene (Tet-5), 1,5-dichloro, 2-formyl, 1-indene (Tet-20) and 1-chloro, 2-formyl, 5,6-methylenedioxy, and 1-indene (Tet-21) exhibited antistaphylococcal activity along with sortase A inhibition. The results also indicate the possible role of these leads in other reactions essential for cell viability.
authors.affiliation: Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Kukrail Picnic Spot Road, P.O: CIMAP, Lucknow, 226015, U.P., India, amangenomics@gmail.com.
authors.forename: Amandeep Kaur
authors.initials: AK
authors.lastname: Kahlon
authors.forename: Arvind S
authors.initials: AS
authors.lastname: Negi
authors.forename: Ruma
authors.initials: R
authors.lastname: Kumari
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Srivastava
authors.forename: Shiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D003546:Cysteine Endopeptidases / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007192:Indenes / Q000494:pharmacology* / Q000633:toxicity; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D007192:Indenes; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases